About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.2631G>C, p.(Trp877Cys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen PALB2 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This missense variant changes PALB2 p.Trp877 to cysteine. The PALB2 VCEP applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism and pathogenic missense variants are thought to be exceedingly rare.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically and no rule matched the adjudicated criteria.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,614,170 alleles
gnomAD v4.1: 1 / 1,614,170 alleles. Recorded AF 6.19513e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PALB2 VCEP v1.2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 6 not met · 4 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The PALB2 c.2631G>C (p.Trp877Cys, p.W877C) variant has not been observed in COSMIC and has been reported in ClinVar as likely benign by a single clinical laboratory.
In population data, this variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at 1/1,614,170 alleles (0.00006%), with a highest observed South Asian frequency of 1/91,090 alleles (0.00110%), which is below the PALB2 BS1 and BA1 thresholds but above the PALB2 PM2 under-represented subpopulation exception threshold for a singleton observation.
In silico splice prediction does not support a clinically significant splice effect, with a SpliceAI maximum delta score of 0.17, which is below the PALB2 PP3 threshold of 0.2.
No criteria match.
Met · 1
BP1 SupportingThis missense variant changes PALB2 p.Trp877 to cysteine. The PALB2 VCEP applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism and pathogenic missense variants are thought to be exceedingly rare. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- NP_078951.2:p.(Trp877Cys)
- PALB2 BP1 applies to all missense variants.
Sources
Not met · 6 · evaluated, threshold not reached
BS1 This variant is present in gnomAD v4.1 at 1/1,614,170 alleles (0.00006%), with a highest observed population frequency of 1/91,090 alleles in South Asian individuals (0.00110%). These values are below the PALB2 BS1 threshold of >0.01%, so BS1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.01% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 total AF 0.00006% (1/1614170)
- gnomAD v4.1 South Asian AF 0.00110% (1/91090)
Sources
PM2 This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,614,170 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of ≤ 0.000333%. However, the highest observed frequency is a single South Asian allele at 1/91,090 (0.00110%), which exceeds the PALB2 under-represented subpopulation exception threshold, so PM2_Supporting is not applied. Details ▾Hide ▴
Rule
Use as PM2_Supporting when frequency ≤ 1/300,000 (0.000333%) in gnomAD v4, with exception for under-represented sub-populations with n=1 but frequency >0.0003%.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AF 0.00006% (1/1614170)
- gnomAD v4.1 South Asian AF 0.00110% (1/91090, AC=1)
Sources
PS4 No PALB2 case-control data were identified showing a significant enrichment of this variant in affected individuals, and ClinVar contains only a single likely benign submitter. Therefore the PALB2 PS4 threshold is not met. Details ▾Hide ▴
BA1 This variant is present in gnomAD v4.1 at 0.00006% overall and 0.00110% in the highest observed population, both of which are below the PALB2 BA1 threshold of >0.1%. BA1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.1% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 total AF 0.00006% (1/1614170)
- gnomAD v4.1 South Asian AF 0.00110% (1/91090)
Sources
PVS1 Germline loss of function is an established disease mechanism for PALB2, but this variant is a missense substitution p.(Trp877Cys) and does not fall into the PALB2 or generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice variants. PVS1 is therefore not applied. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree.
Evidence considered
- PALB2 PVS1 eligible at gene level
- Variant bucket: other
- Not a nonsense, frameshift, or canonical splice variant
Sources
PP3 SpliceAI shows a maximum delta score of 0.17 for this missense variant, which is below the PALB2 PP3 splicing threshold of ≥ 0.2. PP3 is not met. Details ▾Hide ▴
Rule
For splicing, apply when SpliceAI ≥ 0.2 for silent, missense/in-frame, and qualifying intronic variants; do not use PP3 for missense protein prediction.
Evidence considered
- SpliceAI DS_AG 0.17
- SpliceAI max delta score 0.17
Sources
Not assessed · 4 · no assessment recorded
BS4 No quantitative segregation data or Bayes factor data were identified for this variant, so the PALB2 BS4 thresholds cannot be evaluated. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1; lower strengths permitted at less extreme thresholds.
Evidence considered
- PALB2 BS4 requires LOD ≤ -1.28, ≤ -0.64, or ≤ -0.32, or corresponding Bayes factor thresholds.
Still missing
- Segregation data with LOD score or Bayes factor
Sources
PM3 No Fanconi anemia proband data or phase-confirmed trans observations with a pathogenic PALB2 variant were identified, so PM3 cannot be assigned. Details ▾Hide ▴
Rule
Apply PM3 using Fanconi anemia point tables; Supporting = 1 point, Moderate = 2 points, Strong ≥ 4 points, Very Strong ≥ 8 points.
Evidence considered
- PALB2 PM3 uses point-based scoring for recessive disease.
Still missing
- Fanconi anemia case data
- Phase-confirmed in trans observations
Sources
BS2 No data were identified showing this variant in informative unaffected individuals under the PALB2 Fanconi anemia BS2 scoring framework, so BS2 cannot be evaluated. Details ▾Hide ▴
Rule
Apply BS2 using Fanconi anemia point tables; Supporting = 1 point, Moderate = 2 points, Strong ≥ 4 points.
Evidence considered
- PALB2 BS2 uses point-based scoring and excludes general population datasets such as gnomAD.
Still missing
- Informative unaffected individual data
- BS2 point-based evidence
Sources
PP1 No segregation data with affected relatives, LOD score, or Bayes factor were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
Supporting at LOD ≥ 0.3 or Bayes factor ≥ 2:1; stronger levels require higher thresholds.
Evidence considered
- PALB2 PP1 requires quantitative segregation evidence.
Still missing
- Segregation data with LOD score or Bayes factor
Sources
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PM4 N/AThis is a missense substitution, not an in-frame insertion/deletion or stop-loss variant, and PALB2 VCEP marks PM4 as not applicable for this context. Details ▾Hide ▴
Rule
Do not use for in-frame insertions or deletions less than a single exon; use for stop-loss variants only.
Evidence considered
- NM_024675.4:c.2631G>C
- NP_078951.2:p.(Trp877Cys)
Sources
BP6 N/ABP6 is not used by the PALB2 VCEP. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- PALB2 VCEP marks BP6 as not applicable.
Sources
BP5 N/ABP5 is not applied in the PALB2 VCEP framework because co-occurrence with other pathogenic variants is not considered sufficiently informative for PALB2. Details ▾Hide ▴
BS3 N/ABS3 is not applied by the PALB2 VCEP for this missense variant framework, and no validated benign functional assay evidence was identified. Details ▾Hide ▴
PP4 N/APP4 is not applied in the PALB2 VCEP framework because PALB2-related cancer predisposition does not have a sufficiently specific phenotype for this criterion. Details ▾Hide ▴
Rule
Do not use for AD disorder; for AR disorder, use PM3 for specific phenotype considerations.
Evidence considered
- PALB2 VCEP marks PP4 as not applicable.
Sources
PM6 N/APM6 is not applied by the PALB2 VCEP. Details ▾Hide ▴
Rule
Do not use for AD or AR disease.
Evidence considered
- PALB2 VCEP marks PM6 as not applicable.
Sources
PM1 N/APM1 is not used for PALB2 because missense pathogenic variation has not been confirmed as a disease mechanism, and no statistically significant hotspot was identified for this residue. Details ▾Hide ▴
Rule
Do not use: missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.
Evidence considered
- Cancer Hotspots: no hotspot row found for W877
Sources
BP7 N/ABP7 is intended for synonymous or qualifying deep intronic variants, whereas this variant is a missense substitution. Details ▾Hide ▴
Rule
Use for synonymous and qualifying deep intronic variants; RNA-based BP7 may be used when lack of aberrant splicing is observed.
Evidence considered
- NP_078951.2:p.(Trp877Cys)
Sources
BP4 N/AAlthough SpliceAI predicts a low splice effect with a maximum delta score of 0.17, the PALB2 VCEP does not apply BP4 for missense variants. BP4 is therefore not used. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: no predicted impact via SpliceAI ≤ 0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.17
Sources
BP2 N/ABP2 is not applied in the PALB2 VCEP framework. Details ▾Hide ▴
PP2 N/APP2 is not used for PALB2 because missense variants are not an established disease mechanism in this framework. Details ▾Hide ▴
PS3 N/APS3 is not applied by the PALB2 VCEP for this context, and no validated damaging functional assay evidence was identified for this variant. Details ▾Hide ▴
BP3 N/AThis is not an in-frame insertion or deletion in a repetitive region, and BP3 is not applicable in the PALB2 VCEP framework. Details ▾Hide ▴
PP5 N/APP5 is not used by the PALB2 VCEP. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- PALB2 VCEP marks PP5 as not applicable.
Sources
PM5 N/APM5_Supporting in PALB2 is restricted to truncating or qualifying splice variants upstream of p.Tyr1183 and is not used for missense changes, so PM5 does not apply to p.(Trp877Cys). Details ▾Hide ▴
Rule
Use as PM5_Supporting for qualifying truncating or splice variants upstream of p.Tyr1183; do not use for missense changes.
Evidence considered
- NP_078951.2:p.(Trp877Cys)
Sources
PS2 N/APS2 is not applied by the PALB2 VCEP for PALB2-related cancer predisposition. Details ▾Hide ▴
Rule
Do not use for AD or AR disease.
Evidence considered
- PALB2 VCEP marks PS2 as not applicable.
Sources
PS1 N/AThe PALB2 VCEP does not use PS1 for missense substitutions, and no PALB2 PS1 splicing-table evidence was identified for this variant. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: use PALB2 PS1 splicing table.
Evidence considered
- Missense variant p.(Trp877Cys)
- SpliceAI max delta score 0.17
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.2631G>C
- Protein (HGVS p.)
- NP_078951.2:p.(Trp877Cys)
- GRCh38
- chr16:23626353 C>G
- GRCh37
- chr16:23637674 C>G
Gene diagram
Every interpreted variant in PALB2, mapped onto the exon structure of NM_024675.4. Select a row to find it on the plot.
PALB2NM_024675.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PALB2
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,614,170 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,170 alleles · 0 hom
| South Asian1 / 91,090 | 1.1e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19513e-07; MAF= 0.00006%, 1/1614170 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09782e-05; MAF= 0.00110%, 1/91090 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI shows a maximum delta score of 0.17 for this missense variant, which is below the PALB2 PP3 splicing threshold of ≥ 0.2. PP3 is not met. Details ▾Hide ▴
Rule
For splicing, apply when SpliceAI ≥ 0.2 for silent, missense/in-frame, and qualifying intronic variants; do not use PP3 for missense protein prediction.
Evidence considered
- SpliceAI DS_AG 0.17
- SpliceAI max delta score 0.17
Sources
BP7 N/ABP7 is intended for synonymous or qualifying deep intronic variants, whereas this variant is a missense substitution. Details ▾Hide ▴
Rule
Use for synonymous and qualifying deep intronic variants; RNA-based BP7 may be used when lack of aberrant splicing is observed.
Evidence considered
- NP_078951.2:p.(Trp877Cys)
Sources
BP4 N/AAlthough SpliceAI predicts a low splice effect with a maximum delta score of 0.17, the PALB2 VCEP does not apply BP4 for missense variants. BP4 is therefore not used. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: no predicted impact via SpliceAI ≤ 0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.17
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,614,170 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1526222356
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3413456/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23637674-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23626353-C-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.2631…
- OncoKB ↗www.oncokb.org/gene/PALB2/W877C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.2631G%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19513e-07; MAF= 0.00006%, 1/1614170 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09782e-05; MAF= 0.00110%, 1/91090 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.